EP3073999A1 - Crystalline form i of ibrutinib - Google Patents

Crystalline form i of ibrutinib

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Publication number
EP3073999A1
EP3073999A1 EP14866302.4A EP14866302A EP3073999A1 EP 3073999 A1 EP3073999 A1 EP 3073999A1 EP 14866302 A EP14866302 A EP 14866302A EP 3073999 A1 EP3073999 A1 EP 3073999A1
Authority
EP
European Patent Office
Prior art keywords
crystalline form
ibrutinib
ray powder
powder diffraction
diffraction pattern
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP14866302.4A
Other languages
German (de)
French (fr)
Other versions
EP3073999B1 (en
EP3073999A4 (en
Inventor
Minhua Chen
Yanfeng Zhang
Chaohui YANG
Xiaoyu Zhang
Fei Lu
Heng GE
Peng Wang
Pixu Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SUZHOU PENGXU PHARMATECH Co Ltd
Crystal Pharmatech Co Ltd
Original Assignee
Suzhou Pengxu Pharmatech Co Ltd
Crystal Pharmatech Inc
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Application filed by Suzhou Pengxu Pharmatech Co Ltd, Crystal Pharmatech Inc filed Critical Suzhou Pengxu Pharmatech Co Ltd
Priority to PL14866302T priority Critical patent/PL3073999T3/en
Publication of EP3073999A1 publication Critical patent/EP3073999A1/en
Publication of EP3073999A4 publication Critical patent/EP3073999A4/en
Application granted granted Critical
Publication of EP3073999B1 publication Critical patent/EP3073999B1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This invention relates to a novel crystalline form of ibrutinib, and pharmaceutical compositions, methods of preparation, and method of uses thereof.
  • Bruton's tyrosine kinase is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells and a key regulator of B-cell development, activation, signaling, and survival. It plays an essential role in the
  • B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses.
  • BCR cell surface B-cell receptor
  • BTK contributes to the proliferation and survival of B cells, which are the white blood cells that turn malignant in mantle cell lymphoma.
  • Ibrutinib is the first BTK inhibitor approved by the U.S. Food and Drug
  • Ibrutinib has a structure of formula (I), with a chemical name as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-
  • ibrutinib Polymorphism of ibrutinib has been reported in WO2013184572, which discloses six crystalline forms of ibrutinib, including 3 anhydrous forms and 3 solvates (i.e., methyl isobutyl ketone solvate, toluene solvate, and methanol solvate, respectively), obtained through screening a large number of solvent systems, including their mixtures.
  • the solvate forms are not suitable for use directly in dosage forms.
  • the present invention provides a surprisingly discovered new crystalline form of ibrutinib having desired pharmacological properties, for example, higher stability and solubility and low hygroscopicity, which make it more suitable for use in dosage forms to achieve desired bioavailability and therapeutic effects.
  • the crystalline form can also be prepared using simple process in a low cost.
  • the present invention provides a crystalline form of ibrutinib, designated as Form I.
  • the present invention provides process for preparation of ibrutinib
  • the present invention provides pharmaceutical compositions comprising the crystalline Form I of ibrutinib and a pharmaceutically acceptable carrier.
  • the present invention provides a method of using crystalline Form I of ibrutinib in the manufacture of a medicament for treatment of a disease or disorder in connection with BTK activities.
  • the present invention provides a method of treating a disease or disorder in connection with BTK activities, comprising administering to a subject in need thereof a pharmaceutical composition comprising crystalline Form I of ibrutinib.
  • FIG. 1 shows a representative X-ray powder diffraction (XRPD) pattern of crystalline Form I.
  • FIG. 2 shows a representative differential scanning calorimetric (DSC) thermogram of crystalline Form I.
  • FIG. 3 shows a representative thermal gravimetric analysis (TGA) thermogram of crystalline Form I.
  • FIG 4 shows a representative dynamic vapor sorption (DVS) isotherm plot of crystalline Form I.
  • FIG. 5 shows the change in the XRPD pattern of Form I when stored at 25 °C/60%
  • the present invention provides a new crystalline form of ibrutinib, which has a higher solubility under physiological conditions than crystalline Form A of WO2013184572, and thus provides various advantages, such as enhanced bioavailability and reduced drug loading.
  • the new crystalline form is physically and chemically stable, is not hygroscopic and does not become deliquescent at a high humidity, and is therefore convenient for long-term storage.
  • the new crystalline form can be prepared using a simple process in a low cost, which is also highly valuable for further optimization and development of the drug in the future.
  • the present invention provides a crystalline form of ibrutinib, designated as Form I.
  • the crystalline Form I is characterized by an X-ray powder diffraction pattern comprising the following 2 ⁇ values measured using CuKa radiation: 5.2° ⁇ 0.2°, 17.6° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
  • the crystalline Form I is characterized by an X-ray powder diffraction pattern further comprising the following 2 ⁇ values measured using CuKa radiation: 19.3° ⁇ 0.2°, 20.8° ⁇ 0.2°, and 22.4° ⁇ 0.2°.
  • the crystalline Form I is characterized by an X-ray powder diffraction pattern further comprising the following 2 ⁇ values measured using CuKa radiation: 16.2° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 23.0° ⁇ 0.2°.
  • the crystalline Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
  • the crystalline Form I has a differential scanning calorimetric thermogram substantially as shown in FIG. 2, which exhibits an endothermic peak at about 135.1 °C.
  • the crystalline Form I has a thermal gravimetric analysis thermogram substantially as shown in FIG. 3, which exhibits about 0.5% weight loss up to 120 °C, suggesting that the crystalline form is substantially unsolvated and anhydrous.
  • the present invention provides a process for preparation of ibrutinib Form I, comprising: dissolving ibrutinib in alcohol, ether, or ketone, or a mixture or alcohol, ether, or ketone with an alkane; and crystallizing said Form I from the solution, either by equilibration under ambient conditions or by controlled cooling.
  • said dissolving is conducted in a mixed solvent system comprising an alcohol and an alkane.
  • said mixed solvent system comprises 2-propanol and n-heptane.
  • the present invention provides solid pharmaceutical compositions comprising ibrutinib Form I.
  • Form I of ibrutinib together with one or more pharmaceutically acceptable excipients of the present invention may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions.
  • the present invention provides a method for treating cancer in a mammal, comprising administering a therapeutically effective amount of ibrutinib Form I.
  • the cancer is a B cell malignancy.
  • the cancer is a B cell malignancy selected from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.
  • the present invention provides use of ibrutinib Form I in the manufacture of a medicament for the treatment of a disease or disorder related to BTK activities.
  • the disease or disorder is a B cell malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • DLBCL diffuse large B Cell lymphoma
  • multiple myeloma multiple myeloma
  • X-ray Powder diffraction Analytical Instrument: Panalytical Empyrean.
  • the X-ray powder diffraction was conducted by mounting a sample of the crystalline material on a Si single crystal low-background holder and spreading out the sample into a thin layer with the aid of a microscope slide. The 2 ⁇ position was calibrated against Panalytical 640 Si powder standard.
  • the collimated X-ray source was passed through a programmed divergence slit set at 10 mm and the reflected radiation directed through a 5.5 mm anti-scatter slit.
  • the sample was exposed for 16.3 seconds per 0.013° 2-theta increment (continuous scan mode) over the range 3 degrees to 40 degrees 2-theta in theta-theta mode.
  • the running time was 3 minutes and 57 seconds.
  • the instrument was equipped with a RTMS detector (X'Celerator). Control and data capture was by means of a Dell Optiplex 780 XP operating with data collector software.
  • Heating rate 10 °C per minute.
  • Heating rate 10 °C per minute.
  • Purge gas nitrogen.
  • Dynamic Vapor Sorption was measured via a SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25°C were calibrated against deliquescence point of LiCl, Mg(N0 3 )2 and KC1. Typical Parameters for DVS test are listed below.
  • RH range 0% RH to 95% RH
  • Hygroscopicity criteria applied in this example refer to the standard in European pharmacopoeia:
  • deliquescent sufficient water is absorbed to form a liquid

Abstract

Crystalline Form I of ibrutinib, processes for its preparation, pharmaceutical compositions comprising the new Form, and use of Form I of ibrutinib for treating or delaying diseases or disorders related to activity of Bruton's tyrosine kinase (BTK) proteins are disclosed. The novel Form was characterized by X-ray powder diffraction, differential scanning calorimetry, and other techniques. It can be readily prepared and is suitable for use in the preparation of solid dosage forms.

Description

CRYSTALLINE FORM I OF IBRUTINIB
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. § 119(a) to Chinese Patent Application No. 201310616065.4, filed on November 27, 2013, and Application No. 201410542609.1, filed on October 14, 2014, both of which are herein incorporated by reference in their entireties.
FIELD OF THE INVENTION
This invention relates to a novel crystalline form of ibrutinib, and pharmaceutical compositions, methods of preparation, and method of uses thereof. BACKGROUND OF THE INVENTION
Bruton's tyrosine kinase (BTK) is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells and a key regulator of B-cell development, activation, signaling, and survival. It plays an essential role in the
B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses. Thus, among others, BTK contributes to the proliferation and survival of B cells, which are the white blood cells that turn malignant in mantle cell lymphoma.
Ibrutinib is the first BTK inhibitor approved by the U.S. Food and Drug
Administration for the treatment of mantle cell lymphoma. Ibrutinib has a structure of formula (I), with a chemical name as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-
1 H-pyrazolo [3 ,4-d]pyrimidin- 1 -yljpiperidin- 1 -yl]prop-2-en- 1 -one.
(I)
Polymorphism of ibrutinib has been reported in WO2013184572, which discloses six crystalline forms of ibrutinib, including 3 anhydrous forms and 3 solvates (i.e., methyl isobutyl ketone solvate, toluene solvate, and methanol solvate, respectively), obtained through screening a large number of solvent systems, including their mixtures. The two better-studied unsolvated forms of ibrutinib were reported to have low solubility (Form A 0.013 mg/mL at pH = 8 and Form B 0.0096 mg/mL at pH = 7.42). Moreover, the solvate forms are not suitable for use directly in dosage forms.
Therefore, new crystalline forms of ibrutinib, in particular stable unsolvated polymorphs with superior pharmacological properties remain a great need.
SUMMARY OF THE INVENTION
The present invention provides a surprisingly discovered new crystalline form of ibrutinib having desired pharmacological properties, for example, higher stability and solubility and low hygroscopicity, which make it more suitable for use in dosage forms to achieve desired bioavailability and therapeutic effects. The crystalline form can also be prepared using simple process in a low cost.
In one aspect, the present invention provides a crystalline form of ibrutinib, designated as Form I.
In another aspect, the present invention provides process for preparation of ibrutinib
Form I.
In another aspect, the present invention provides pharmaceutical compositions comprising the crystalline Form I of ibrutinib and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of using crystalline Form I of ibrutinib in the manufacture of a medicament for treatment of a disease or disorder in connection with BTK activities.
In another aspect, the present invention provides a method of treating a disease or disorder in connection with BTK activities, comprising administering to a subject in need thereof a pharmaceutical composition comprising crystalline Form I of ibrutinib.
Other aspects and embodiments of the present invention will be further illustrated in the following description and examples.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a representative X-ray powder diffraction (XRPD) pattern of crystalline Form I.
FIG. 2 shows a representative differential scanning calorimetric (DSC) thermogram of crystalline Form I. FIG. 3 shows a representative thermal gravimetric analysis (TGA) thermogram of crystalline Form I.
FIG 4 shows a representative dynamic vapor sorption (DVS) isotherm plot of crystalline Form I.
FIG. 5 shows the change in the XRPD pattern of Form I when stored at 25 °C/60%
RH for 180 days (FIG. 5b) and 40 °C/75% RH for 180 days (FIG. 5c) as compared to the original Form I (FIG. 5 a).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a new crystalline form of ibrutinib, which has a higher solubility under physiological conditions than crystalline Form A of WO2013184572, and thus provides various advantages, such as enhanced bioavailability and reduced drug loading. The new crystalline form is physically and chemically stable, is not hygroscopic and does not become deliquescent at a high humidity, and is therefore convenient for long-term storage. Moreover, the new crystalline form can be prepared using a simple process in a low cost, which is also highly valuable for further optimization and development of the drug in the future.
In one aspect, the present invention provides a crystalline form of ibrutinib, designated as Form I.
In one embodiment, the crystalline Form I is characterized by an X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 5.2°±0.2°, 17.6°±0.2°, and 22.1°±0.2°.
In another embodiment, the crystalline Form I is characterized by an X-ray powder diffraction pattern further comprising the following 2Θ values measured using CuKa radiation: 19.3°±0.2°, 20.8°±0.2°, and 22.4°±0.2°.
In another embodiment, the crystalline Form I is characterized by an X-ray powder diffraction pattern further comprising the following 2Θ values measured using CuKa radiation: 16.2°±0.2°, 18.1°±0.2°, 18.9°±0.2°, and 23.0°±0.2°.
The crystalline Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
The crystalline Form I has a differential scanning calorimetric thermogram substantially as shown in FIG. 2, which exhibits an endothermic peak at about 135.1 °C. The crystalline Form I has a thermal gravimetric analysis thermogram substantially as shown in FIG. 3, which exhibits about 0.5% weight loss up to 120 °C, suggesting that the crystalline form is substantially unsolvated and anhydrous.
In another aspect, the present invention provides a process for preparation of ibrutinib Form I, comprising: dissolving ibrutinib in alcohol, ether, or ketone, or a mixture or alcohol, ether, or ketone with an alkane; and crystallizing said Form I from the solution, either by equilibration under ambient conditions or by controlled cooling.
In some embodiments, said dissolving is conducted in a mixed solvent system comprising an alcohol and an alkane.
In some embodiments, said mixed solvent system comprises 2-propanol and n-heptane.
In another aspect, the present invention provides solid pharmaceutical compositions comprising ibrutinib Form I.
Form I of ibrutinib together with one or more pharmaceutically acceptable excipients of the present invention may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions.
In another aspect, the present invention provides a method for treating cancer in a mammal, comprising administering a therapeutically effective amount of ibrutinib Form I. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is a B cell malignancy selected from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.
In another aspect, the present invention provides use of ibrutinib Form I in the manufacture of a medicament for the treatment of a disease or disorder related to BTK activities. In an embodiment, the disease or disorder is a B cell malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma. The following non-limiting examples further illustrate certain aspects of the presen invention.
EXAMPLES
X-ray Powder diffraction (XRPD) Analytical Instrument: Panalytical Empyrean. The X-ray powder diffraction was conducted by mounting a sample of the crystalline material on a Si single crystal low-background holder and spreading out the sample into a thin layer with the aid of a microscope slide. The 2Θ position was calibrated against Panalytical 640 Si powder standard. The sample irradiated with X-rays generated by a copper long-fine focus tube operated at 45 kV and 40 mA with a wavelength of Kal = 1.540589 angstroms and Ka2 = 1.544426 angstroms (Kal/ Ka2 intensity ratio is 0.50). The collimated X-ray source was passed through a programmed divergence slit set at 10 mm and the reflected radiation directed through a 5.5 mm anti-scatter slit. The sample was exposed for 16.3 seconds per 0.013° 2-theta increment (continuous scan mode) over the range 3 degrees to 40 degrees 2-theta in theta-theta mode. The running time was 3 minutes and 57 seconds. The instrument was equipped with a RTMS detector (X'Celerator). Control and data capture was by means of a Dell Optiplex 780 XP operating with data collector software.
Persons skilled in the art of X-ray powder diffraction will realize that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios that may affect analysis of samples. The skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the difiractometer and the zero calibration of the difiractometer. The surface planarity of the sample may also have a small effect. Hence the diffraction pattern data presented are not to be taken as absolute values. Differential Scanning Calorimetry (DSC)
Analytical Instrument: TA Instruments Q2000 DSC.
Heating rate: 10 °C per minute.
Purge gas: nitrogen Thermal Gravimetric Analysis (TGA)
Analytical Instrument: TA Instruments Q5000 TGA.
Heating rate: 10 °C per minute.
Purge gas: nitrogen.
Dynamic Vapor Sorption (DVS)
Dynamic Vapor Sorption (DVS) was measured via a SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25°C were calibrated against deliquescence point of LiCl, Mg(N03)2 and KC1. Typical Parameters for DVS test are listed below.
Parameters for DVS test
Parameters Settings/Values
Temperature 25 °C
Sample size 10 - 20 mg
Gas and flow rate N2, 200 mL/min
dm/dt 0.002%/min
Min. dm/dt stability duration 10 min
Max. equilibrium time 180 min
RH range 0% RH to 95% RH
10% RH from 0% RH to 90% RH
RH step size
5% RH from 90% RH to 95% RH
Example 1. Preparation of ibrutinib crystalline Form I
In 15 mL of 2-propanol/n-heptane (2:3, v/v) was dissolved 513 mg of ibrutinib. The solution was equilibrated under ambient conditions for 24 h, and Form I was obtained, which was analyzed by XRPD, DSC, and TGA. The XRPD pattern of Form I is displayed in FIG. 1. The XRPD data of Form I produced in this example are listed in Table 1.
The XRPD pattern of Form I obtained from this Example is displayed in FIG. 1 , the DSC thermogram of Form I obtained from this Example is displayed in FIG. 2; and the TGA thermogram of Form I obtained from this Example is displayed in FIG. 3. Table 1
Example 2. Preparation of ibrutinib crystalline Form I
In 1.6 mL of 2-propanol/n-heptane (1 :5, v/v) was dissolved 48.2 mg of ibrutinib to get a saturated solution of ibrutinib under 50 °C. The solution was cooled from 50 °C to 5 °C at a cooling rate of 0.1 °C/min, and Form I was produced. The XRPD data of Form I produced in this example are listed in Table 2.
Table 2
16.36 5.42 19.08
16.94 5.23 7.01
17.31 5.12 17.28
17.57 5.05 28.02
17.96 4.93 27.91
18.03 4.92 34.36
18.82 4.72 31.86
19.25 4.61 66.12
20.73 4.28 35.16
22.03 4.04 100.00
22.40 3.97 26.54
22.94 3.88 42.42
23.84 3.73 11.05
24.46 3.64 3.60
25.00 3.56 12.43
25.84 3.45 13.98
26.27 3.39 3.22
27.80 3.21 4.80
28.43 3.14 1.75
28.87 3.09 9.22
29.37 3.04 2.72
30.28 2.95 7.21
30.97 2.89 9.78
32.14 2.78 4.45
32.76 2.73 5.35
33.27 2.69 1.69
33.83 2.65 4.33
35.30 2.54 1.30
35.63 2.52 2.31
36.49 2.46 1.39
38.93 2.31 1.48 Example 3. Preparation of ibrutinib crystalline Form I
In 0.5 mL of acetone was dissolved 12.7 mg of ibrutinib, followed by the slow addition of 2.0 mL of n-heptane. The suspension was stirred at a rate of 1000 rpm for one day, and Form I was produced. The XRPD data of Form I produced in this example are listed in Table 3.
Table 3
27.96 3.19 4.60
28.94 3.09 4.30
30.34 2.95 5.67
31.02 2.88 4.58
32.18 2.78 1.93
32.80 2.73 2.82
33.87 2.65 1.92
35.68 2.52 1.48
36.55 2.46 0.94
37.93 2.37 0.46
Example 4. Kinetic solubility comparison between crystalline Form I of ibrutinib and crystalline Form A (WO2013184572 A 1 )
Kinetic solubility of ibrutinib in crystalline Form I and in crystalline Form A (WO2013184572A1) in fed state simulated intestinal fluid (FeSSIF) and simulated gastric fluid (SGF) were measured using the following procedures:
1. Weigh approximately 30 mg of ibrutinib crystalline Form A or Form I into a tared 4-mL plastic vial and record the actual weight of the compound.
2. Add 3 mL of bio-relevant medium into each vial.
3. Cap the vials and keep all the suspension samples stirring at RT (room temperature) using a rolling incubator at a rate of 25 r/min.
4. Sample at lh, 4h and 24h respectively. About 0.6 mL aliquot of the suspension is transferred per time from solubility vial into a centrifuge filtration tube (pore size of 0.45 μιη).
5. Centrifuge filtration tubes at a rate of 8500 rpm for 3 minutes at RT, collect 0.2 mL of supernatant for HPLC quantification determination and collect the rest of solution for pH measurement, and separate the solid for XRPD characterization.
The results displayed in Table 4 suggest crystalline Form I has higher solubility in comparison to crystalline Form A (WO2013184572Al). Table 4
Example 5. Hygroscopicity assessment of Form I
Hygroscopicity of ibrutinib Form I was investigated using dynamic vapor sorption (DVS). The DVS isotherm plot of Form I displayed in FIG 4 and the detailed data listed in Table 5 show that the sample has 0.19% water uptake under 80%> RH, 25 °C, suggesting Form I is non-hygroscopic.
Table 5
Hygroscopicity criteria applied in this example refer to the standard in European pharmacopoeia:
— deliquescent: sufficient water is absorbed to form a liquid;
— very hygroscopic: increase in mass is equal to or greater than 15 percent;
— hygroscopic: increase in mass is less than 15 percent and equal to or greater than 2 percent;
— slightly hygroscopic: increase in mass is less than 2 percent and equal to or greater than 0.2 percent.
Example 6. Stability assessment of Form I under stress conditions
Two samples of ibrutinib Form I were stored under 25 °C/60%> RH and 40 °C/75%> RH, respectively, with dish open for 180 days. The chemical and physical stabilities of the samples were evaluated by high performance liquid chromatography (HPLC) and XRPD. The XRPD patterns of Form I under stress conditions are displayed in FIG. 5. The result of stability assessment tabulated in Table 6 indicates that Form I is physically and chemically stable under the stress conditions.
Table 6
The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting, the present invention as defined by the claims. As will be readily appreciated by a person skilled in the art, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. All such variations are intended to be included within the scope of the following claims. All references cited herein are incorporated by reference in their entireties.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A crystalline form of ibrutinib, designated as Form I, having an X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 5.2°±0.2°, 17.6°±0.2°, and 22. r±0.2°.
2. The crystalline form of claim 1, wherein the X-ray powder diffraction pattern further comprises the following 2Θ values measured using CuKa radiation: 19.3°±0.2°, 20.8°±0.2°, and 22.4°±0.2°.
3. The crystalline form of claim 1 or 2, wherein the X-ray powder diffraction pattern further comprises the following 2Θ values measured using CuKa radiation: 16.2°±0.2°,
18.1°±0.2°, 18.9°±0.2°, and 23.0°±0.2°.
4. The crystalline form of claim 1, having an X-ray powder diffraction pattern substantially as depicted in FIG. 1.
5. The crystalline form of claim 1, having a differential scanning calorimetric thermogram substantially as depicted in FIG. 2.
6. The crystalline form of claim 1, having a thermal gravimetric analysis thermogram substantially as depicted in FIG. 3.
7. A process for the preparation of ibrutinib Form I, comprising: dissolving ibrutinib in a solvent system selected from the group consisting of alcohol, ether, ketone, a mixture of alcohol with alkane, a mixture of ether and alkane, and a mixture of ketone with alkane to form a solution; and crystallizing said Form I by cooling the solution under ambient conditions or in a controlled manner.
8. The process according to claim 7, wherein said solvent system is a mixture of an alcohol or ketone and an alkane.
9. The process according to claim 8, wherein said alcohol is a lower alcohol, and said alkane is a C4-C10 alkane.
10. The process according to claim 8, wherein the solvent system is a mixture of 2-propanol and n-heptane.
11. The process according to claim 8, wherein said ketone is a C3-C6 ketone, and said alkane is a C4-C10 alkane.
12. The process according to claim 8, wherein the solvent system is a mixture of acetone and n-heptane.
13. A pharmaceutical composition comprising crystalline Form I of ibrutinib and a pharmaceutically acceptable carrier, wherein said crystalline Form I has an X-ray powder diffraction pattern comprising the following 2Θ values measured using CuKa radiation: 5.2°±0.2°, 17.6°±0.2°, and 22.r±0.2°.
14. The pharmaceutical composition of claim 13, wherein the X-ray powder diffraction pattern of said crystalline Form I further comprises the following 2Θ values measured using CuKa radiation: 19.3°±0.2°, 20.8°±0.2°, and 22.4°±0.2°.
15. The pharmaceutical composition of claim 13 or 1414, wherein the X-ray powder diffraction pattern further comprises the following 2Θ values measured using CuKa radiation: 16.2°±0.2°, 18.1°±0.2°, 18.9°±0.2°, and 23.0°±0.2°.
16. The pharmaceutical composition of claim 13, wherein said crystalline Form I has a melting point at about 135.1 °C as measured by differential scanning calorimetry (DSC).
17. The pharmaceutical composition of claim 13, wherein the X-ray powder diffraction pattern of said crystalline Form I has an X-ray powder diffraction pattern substantially as depicted in FIG. 1.
18. A method of treating or delaying the progression or onset of a disease or disorder in connection with activity of a Bruton's tyrosine kinase (BTK), comprising administering to a subject in need thereof a pharmaceutical composition comprising crystalline Form I of ibrutinib.
19. The method of claim 18, wherein said disease or disorder is a B cell malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.
20. Use of crystalline Form I of ibrutinib in the manufacture of a medicament for treating or delaying the progression or onset of a disease or disorder in connection with activity of Bruton's tyrosine kinase (BTK).
21. The use of claim 17, wherein said disease or disorder is a B cell malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and multiple myeloma.
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